Growth hormone (GH) secretion declines during normal aging, resulting in lower circulating levels of insulin-like growth factor (IGF-1). Although the physiologic sequelae to decreased somatotrope function are not fully understood, many of the catabolic changes seen in normal aging, including osteopenia, muscle atrophy, and decreased exercise tolerance, may in part be caused by the decreased action of the GH-IGF-I axis. The age-related decline in the activity of the hypothalamic-somatotrope-IGF axis may thus result in catabolic diathesis leading to falls, fractures, and frailty in the elderly, a syndrome complex which has been named "the somatopause". Previous work has demonstrated that GH and IGF-I decrease fat mass, increase lean body mass and nitrogen retention, and promote whole body and skeletal muscle net protein synthesis. Both GH and high dose IGF-1 increase the birthrate of remodeling osteons. However, low-dose IGF-I may directly increase osteoblastic function without increasing bone resorption, and may therefore provide a useful means to increase bone mass. Moreover, IGF-I may have mood-enhancing effects in the elderly. In order to determine the effects of prolonged GH and IGF-I therapy and to understand the endocrine mechanisms underlying their physiologic effects, three independent investigations into the physiologic role of GH and IGF-I therapy in the somatopause are proposed. In these studies, a major emphasis will be placed on understanding the interactions of estrogen/progestin hormone replacement therapy (HRT) and treatment of the somatopause. Study 1 is a year long, double-blind, randomized, placebo-controlled trial which will explore the interactions of GH, IGF-I and estrogen/progestin therapy on body composition, muscular strength, and muscle growth factor synthesis. Study II will explore endocrine mechanisms underlying the effects of GH and IGF-I therapy on fluid compartments in detail. This experiment will build upon previous studies which unexpectedly demonstrated that both hormones cause dramatic shifts of water into the intracellular space. Study III is a short term study that will examine the role of GH and IGF-1 in protein and lipid metabolism to understand the anabolic action of these hormones in elderly women. This study will help provide a mechanistic basis for the finding obtained in Study I. These studies will provide the first investigation of the interactions of hormone replacement therapies for the somatopause (GH and IGF-I) and the menopause (estrogen and progestin) and will lead to novel pharmacologic approaches for the treatment of frailty in the elderly.